Effects of Simulated Weightlessness on Metabolizing Enzymes and Pharmacokinetics of Folic Acid in SD Rats

Abstract

Folic acid (FA) affect human physiology and drug metabolism. Up to now, the effect of microgravity on the pharmacokinetics of FA remains unclear. The pharmacokinetics of FA in Sprague-Dawley (SD) rats are laying a foundation for safe medicine administration of astronauts. Proteins expression of such FA metabolic enzymes as Methyltetrahydrofolate reductase (MTHFR), Cystathionine beta synthase (CBS) and Methionine synthase (MS) in a variety of organs was analyzed with Western-Blot, and mRNA expression was detected by RT-PCR. The plasma concentration-time profile of FA in normal or tail-suspended SD rats was acquired by liquid chromatography-tandem mass spectrometry (LC-MS/MS) after oral administration of FA. Area under curve (AUC) and C max of FA in SD rats decreased significantly with extending period of tail-suspension. In terms of expressed level of metabolic enzymes over four suspension terms, as well as the level of the corresponding mRNAs, the following regularities were found: an obvious sharp decline of MTHFR tissue in kidney, a time-dependent increase of CBS in liver tissue and duodenum tissues, the resemblance of MS fluctuation to that of CBS in tested tissues. A four-week simulated microgravity of SD rats exhibits an unequivocal diminish of bioavailability of FA, and simulated microgravity shows a varying effect on the expression of FA-metabolizing enzyme in a variety of tissues.

Hepatology in space: Effects of spaceflight and simulated microgravity on the liver

“…10 Alterations in biotransformation capacity may be accompanied by in the pharmacokinetic behaviour of folic acid was reported in tail suspended rats after 4 weeks resulting from alterations in metabolizing enzymes. 40 Weightlessness simulated through tail suspension reduced clearance of antipyrine by almost 50% in male rats.…”

Evaluation of In Vivo Folic Acid Bioavailability in Different Mouse Strains Using Enzymatic Digestion Combined with Ultra Performance Liquid Chromatography

“…Folic acid bioavailability was reliant on several factors, as discussed previously regarding the food or host. − In the current study, an in vitro model was used to explore the effects of food source, food matrix, food processing method, and conversion of polyglutamate folic acid on folic acid bioavailability. Two primary animal-based methods were used to assess folic acid bioavailability: short-term kinetics , and long-term studies. , Due to variations in the bioavailability of folic acid among different mouse strains, which rendered long-term experiments more appropriate, the current study employed a ten-day cycle experiment . The mice were administered folic acid at a rate of 4 mg/kg on a daily basis.…”

Effects of long‐term simulated microgravity on liver metabolism in rhesus macaques

“…3 Spaceflight has a significant impact on the liver, at least in rodent models, in addition to muscle atrophy, bone loss, changes in the gastrointestinal tract, and cardiovascular system. [4][5][6][7][8][9][10][11][12][13] The liver samples of mice flown aboard the Space Transportation System (STS)-135 (13.5-day flight) revealed accumulation of lipid droplets and infiltration of inflammatory cells by histology, elevated triglyceride and ophthalmic, decreased glutathione and retinol, decreased oxidative defense machinery, and activation of peroxisome proliferatoractivated receptor (PPAR) pathways by metabolomic and transcriptomic analyses. 5,6,14 Similar results were obtained in mice with spaceflights with various lengths (STS-118 [13-day], RR-1 CASIS [21-day], RR-1 NASA [37-day], and Bion-M1 [30-day]), and longer space duration was associated with further upregulation of the fatty acid metabolic process pathways.…”

“…Spaceflight has a significant impact on the liver, at least in rodent models, in addition to muscle atrophy, bone loss, changes in the gastrointestinal tract, and cardiovascular system 4–13 . The liver samples of mice flown aboard the Space Transportation System (STS)‐135 (13.5‐day flight) revealed accumulation of lipid droplets and infiltration of inflammatory cells by histology, elevated triglyceride and ophthalmic, decreased glutathione and retinol, decreased oxidative defense machinery, and activation of peroxisome proliferator‐activated receptor (PPAR) pathways by metabolomic and transcriptomic analyses 5,6,14 .…”